Internet-Delivered Exposure and Response Prevention for Pediatric Tourette Syndrome

Key Points Question Is therapist-supported, internet-delivered exposure and response prevention (ERP) for youths with Tourette syndrome or chronic tic disorder efficacious and cost-effective in the long term, compared with therapist-supported, internet-delivered psychoeducation? Findings In this follow-up study of a randomized clinical trial, 221 youths with Tourette syndrome or chronic tic disorder initially randomly allocated to therapist-supported, internet-delivered ERP or psychoeducation showed no tic severity change between the 3- and 12-month follow-up and no significant between-group differences. The use of ERP was cost-effective from a health care sector perspective (including health care resource use in and outside the study), but results were less conclusive from a societal perspective (additionally including costs beyond health care). Meaning These results suggest that although ERP was not superior to psychoeducation alone in reducing tic severity at the end of the follow-up period, it is likely cost-effective.


Introduction
Behavior therapy (BT) is a first-line intervention for Tourette syndrome (TS) and chronic tic disorder (CTD). 1,24][5] Both treatments are typically delivered in person, and thus, their availability is limited. 6,7][10][11] In a large UK randomized clinical trial (RCT)-the Online Remote Behavioural Intervention for Tics (ORBIT) trial 12 -224 young individuals with TS or CTD were randomized to 1 of two 10-week therapist-supported, internet-delivered interventions: ERP and psychoeducation.At the primary end point (posttreatment), internet-delivered ERP was superior to psychoeducation in reducing tic severity, requiring only minimal therapist resources. 13These results were maintained long-term (about 15 months after treatment). 14In a largely identical study involving 221 participants conducted in Sweden, 15 internet-delivered ERP was not superior to psychoeducation in reducing tic severity at the primary end point (3 months posttreatment), but the ORBIT trial results were replicated on a secondary measure of treatment response. 16Overall, within-group results indicated clinically relevant improvements from both interventions, requiring minimal therapist time.
Long-term follow-up is particularly important in the evaluation of treatments for TS and CTD, as tics naturally wax and wane over time. 2 Aside from the ORBIT trial, 14 previous research has been restricted to a short follow-up duration (ie, up to 6 months after treatment) 4,5 or following up only initial treatment responders. 3,4The present study reports on the prespecified 15 12-month follow-up of 221 participants in the Swedish RCT 16 to establish the long-term efficacy and cost-effectiveness of internet-delivered ERP compared with psychoeducation.

Design
This prespecified study reported controlled data from the 6-month and 12-month follow-up assessements of the participants in the original RCT (Figure 1).For further details on the study design, see the published study protocol, 15 the primary publication, 16 and the appended research protocol (Supplement 1).Ethical approval was obtained from the Swedish Ethical Review Authority.
Written informed consent was collected from all participants and their legal guardians.Reporting

Participants and Randomization
Eligible participants were aged 9 to 17 years and had a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) diagnosis of TS or CTD. 19Complete eligibility criteria are presented in eMethods 1 in Supplement 2. Participants were recruited across Sweden through clinician-and selfreferrals.After assessments of tic severity and tic-related impairment (Yale Global Tic Severity Scale; YGTSS) 20 and psychiatric comorbidities (Mini-International Neuropsychiatric Interview for children and adolescents), 21 eligible participants were randomly assigned (1:1) to ERP or psychoeducation using randomly varying block sizes.Randomization was performed through an online service 22 and monitored by an independent clinic trials unit.The ERP intervention was based on published treatment manuals. 24,25In ERP, participants initially practiced tic suppression (response prevention).Once they had gained mastery, they focused on the premonitory urges (ie, bothersome sensations preceding tic expression) to make the tic suppression more challenging (exposure and response prevention).The psychoeducation intervention was based on control interventions used in previous clinical trials of BT for TS and CTD. 3,4This comparator included psychoeducation (ie, about tic disorders and comorbid conditions) and behavioral exercises (eg, healthy habits and everyday routines).Details about both interventions are presented in Supplement 1. Families continued to have online access to all intervention modules (without therapist support) for the full 12-month follow-up period.After the 3-month follow-up, participants were free to pursue any treatment of their choice.

Outcome Measures
The primary outcome measure was the YGTSS-Total Tic Severity Score (YGTSS-TTSS), 20 a semistructured clinician-rated measure of tic severity (scores ranged from 0 to 50, with higher numbers indicating greater tic severity). 26All assessors were trained in the use of the YGTSS-TTSS (Supplement 1).Other clinician-rated measures included the YGTSS impairment score (scores ranged from 0 to 50 points, with higher scores indicating greater tic-related impairment), 20 the Children's Global Assessment Scale (CGAS; scores ranged from 1 to 100 points, with higher scores indicating higher functioning), 27 and the Clinical Global Impression Severity and Improvement scales (CGI-S/I; CGI-S scores ranged from 1 [no symptoms] to 7 [extreme symptoms]; CGI-I scores range from 1 [very much improved] to 7 [very much worse]). 28A score of 1 or 2 (much improved) on the CGI-I was used to define treatment response.Masking procedures are described in eMethods 2 in Supplement 2.
For the 6-month and 12-month follow-up assessements, clinician-rated measures were administered by assessors masked to group allocation via videoconference (385 [92%]), the telephone (29 [7%]) or face-to-face at the clinic (4 [1%]).Follow-up assessments were administered to both the child and at least 1 parent, or in some cases only the child (13 [3%]) or only a parent (54 [13%]).After each assessment, masked assessors recorded a guess of the participant's group allocation.
Self-and parent-reported measures included the Parent Tic Questionnaire (PTQ; scores ranged from 0 to 224 points, with higher scores indicating greater tic severity), 29 the Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life scale (C&A-GTS-QOL; scores ranged from 0 to 135 points, with higher scores indicating lower quality of life), 30 the Obsessive-Compulsive Inventory-Child Version (OCI-CV; scores ranged from 0 to 42 points, with higher scores indicating greater obsessive-compulsive severity), 31 the Short Mood and Feelings Questionnaire child-and parentreported versions (SMFQ-C and SMFQ-P, respectively; scores ranged from 0 to 26 points, with higher scores indicating greater depression), 32 and the KIDSCREEN-10. 33Quality-adjusted life years (QALYs) were obtained through mapping KIDSCREEN-10 33 data to the Child Health Utility 9 Dimensions (CHU9D) utility scores. 34Data on resource use were collected through the parent-reported Trimbos/ iMTA (Institute for Medical Technology Assessment) questionnaire for costs associated with psychiatric illness (TiC-P). 35l self-and parent-reported outcome measures were completed through an online service.
Data quality was monitored by an external clinical trials unit. 23A complete description of all outcome measures is available in Supplement 1.

Health Economic Evaluation
A health economic evaluation was performed using 3 costing perspectives: (1) a health care organization perspective (including direct costs for treatment provided in the study, ie, therapist time), (2) a health care sector perspective (additionally including health care resource use outside the clinic and study, as well as medication costs), and (3) a societal perspective (additionally including

JAMA Network Open | Psychiatry
Internet-Delivered Exposure and Response Prevention for Pediatric Tourette Syndrome costs beyond health care; eg, parents' absenteeism from work).Two analyses were performed for each of the 3 perspectives: a cost-effectiveness analysis (using treatment response rate as the outcome) and a cost-utility analysis (using QALYs as the outcome). 36Incremental cost-effectiveness ratios (ICERs) operationalized as the cost per additional treatment responder or QALY were estimated.Further details on the health economic evaluation are presented in Supplement 1 and eMethods 3 in Supplement 2.

Statistical Analysis
A power calculation was performed for the primary end point analysis of the original study (Supplement 1). 16Statistical analyses followed an a priori published statistical analysis plan (Supplement 1).8][39] First, within-group analyses evaluated whether the treatment effects at the 3-month follow-up were sustained at the 12-month follow-up.Second, between-group analyses investigated potential interaction effects of treatment and time from baseline to the 12-month follow-up.To enable comparisons with previous trials estimating mean differences, complementary intention-to-treat analyses using linear mixed models were performed.Quantile regression, logistic regression, and χ 2 tests were used where appropriate.Effect sizes are presented as differences in median relative to the IQR (for median differences) and as Cohen d (for mean differences). 40

Primary Outcome
Observed medians and means of the YGTSS-TTSS at each assessment point are presented in Table 1.
Data loss on the YGTSS-TTSS was minimal (Table 1 and Figure 1).
During the follow-up phase, tic severity as measured by the YGTSS-TTSS was reduced a mean of 1.24 raw points in the ERP group and 0.99 raw points in the comparator (Table 1).that previously reported improvements 16 on the YGTSS impairment score, the PTQ, the C&A-GTS-QOL, the CGAS, the OCI-CV, the SMFQ-C, and the SMFQ-P at the 3-month follow-up were unchanged up to the 12-month follow-up for both groups (Table 2; eTable 4 in Supplement 2).Similarly, the a Observed values calculated from completer data.
b Defined as therapist-supported, internet-delivered psychoeducation.
c Scores range from to 50 points, with higher numbers indicating greater tic severity.
d Primary end point.
e Scores range from to 50 points, with higher scores indicating greater tic-related impairment.
f Scores range from (no symptoms) to 7 (extreme symptoms).
g Scores range from to 224 points, with higher scores indicating greater tic severity.
h Midtreatment indicates 5 weeks into the treatment.
i Scores range from to 135 points, with higher scores indicating lower quality of life..170.10 (−0.08 to 0.28)
Between-group linear quantile mixed model analyses using data from all 5 assessment points identified no significant interaction effects between treatment and time on any outcome measure (Table 2; eTable 4 in Supplement 2).Results of all complementary linear mixed model analyses are shown in eTable 2 in Supplement 2.

Post Hoc Analyses
To examine the impact of age on treatment outcomes, the total sample was split into 2 groups by median age (9-11 years for 124 participants, and 12-17 years for 97 participants).Tic severity improvements (YGTSS-TTSS) were similar in both age groups, with no differences between the intervention groups (9-11 years, −0.40 [95% CI, −1.49 to 0.71]; P = .48and 12-17 years, −0.32 [95% CI, −1.04 to 0.40]; P = .38).In an additional post hoc analysis stratified by responder status at the primary end point (both groups combined), 82 treatment responders showed no change in tic psychoeducation (50% in the current study, 41% in ORBIT).The somewhat unexpected larger effect of the comparator in our study may be due to a range of reasons, such as a sample population with milder symptom severity and the use of more experienced therapists.Considering that symptoms improved similarly in both groups, the study design cannot rule out that factors other than the provided interventions contributed to the measured effects.Natural improvement over time could be one such explanation, which may be particularly likely in the long-term, given that tics generally decrease with age. 42Such an effect could have contributed to eroding potential differences between the groups, especially for a sample population with relatively mild symptom severity and limited room for improvement.Additional interventions during the follow-up period may also have affected the results.However, although slightly more participants in the comparator group than in the ERP group received additional treatment during the follow-up period, sensitivity analyses excluding participants who had received extra interventions showed no impact on the results.
From the health care organization perspective, direct intervention costs were higher for the ERP intervention than for the comparator ($15.14 per participant).From the wider health care sector perspective (direct intervention costs and other health care costs), ERP was dominant, meaning that it generated more QALYs (and more treatment responders) at a lower cost than the comparator.This has the potential of making the ERP intervention attractive for health care services providing (−0.14 to 0.14) −0.55 (−1.33 to 0.24) Abbreviations: C&A-GTS-QOL, Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life scale; CGI-S, Clinical Global Impression-Severity scale; ERP, exposure and response prevention; PTQ, Parent Tic Questionnaire; TTSS, Total Tic Severity Score; YGTSS, Yale Global Tic Severity Scale.aDefined as therapist-supported, internet-delivered psychoeducation.

Figure 2 .
Figure 2.Estimated Mean Scores on the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTSS) From a Linear Mixed Model Including All 5 Assessment Points25

23
InterventionsBoth interventions were delivered during 10 weeks via an internet platform.Through separate logins, children and parents accessed intervention modules, including self-help texts, illustrations, videos, worksheets, and homework assignments.Therapist support was provided via asynchronous text
From baseline to the 12-month follow-up, tic severity as measured by the YGTSS-TTSS was reduced a mean of 7.32 raw points in the ERP group and 6.28 raw points in the comparator (both statistically significant reductions in within-group analyses; Table1 and Table 2).A between-group linear quantile mixed model found no significant interaction effect between treatment and time on JAMA Network Open | Psychiatry Internet-Delivered Exposure and Response Prevention for Pediatric Tourette Syndrome JAMA Network Open.2024;7(5):e248468.doi:10.1001/jamanetworkopen.2024.8468(Reprinted) May 3, 2024 5/15 Downloaded from jamanetwork.comby guest on 05/05/2024 the YGTSS-

Table 1 .
Observed Medians and Means at All Assessment Points for the Primary Outcome and a Selection of Secondary Outcomes

Table 2 .
Results of Linear Quantile Mixed Models for the Primary Outcome and a Selection of Secondary Outcomes ). B, Includes costs of the ERP or comparator interventions, health care visits, and medication or supplements.C, Includes costs of the ERP or comparator interventions, health care visits, medication or supplements, and other sector costs (eg, productivity losses or child school absenteeism).The probability of the ERP group showing QALY gains at higher costs is in the northeast quadrant; the equivalent probability at lower costs is in the southeast quadrant.The probability of the comparator showing QALY gains at higher costs is in the northwest quadrant; the equivalent probability at lower costs is in the southwest quadrant.Further details on the health economic evaluation eTable 1. Baseline demographics and clinical characteristics for study participants eTable 2. Results of complementary linear mixed models for the primary and secondary outcomes eTable 3. Observed medians and means at all assessment points for additional secondary outcomes eTable 4. Results of linear quantile mixed models for additional secondary outcomes eTable 5. Group allocation guesses and motivations, by assessors eTable 6. Health economic evaluation, baseline outcomes and costs (2021 USD) eTable 7. Unit costs used in the costing of resources, in 2021 USD eTable 8. Cost means and differences from baseline to the 12-month follow-up, after multiple imputation, in 2021 USD eTable 9. Mean CHU9D utility scores per assessment point and total QALYs over the study period, after multiple imputation eTable 10.Outcomes and costs from baseline to the 12-month follow-up, after multiple imputation eFigure 1. Cost-effectiveness planes with treatment response as the outcome for three costing perspectives eFigure 2. Cost-effectiveness acceptability curves with treatment response as the outcome for three costing perspectives eFigure 3. Cost-effectiveness acceptability curves with QALYs as the outcome for three costing perspectives